The National Institutes of Health estimates that over 7 million people suffer from chronic pain specifically related to the temporomandibular (TM) joint. Despite this, there are very few proven effective therapies, especially for patients who do not respond to over the counter anti-inflammatory drugs. Based on the published literature, it is believed that the disease cycle involves injury, followed by the production of inflammatory cytokines, followed by the over expression of matrix metalloproteinases, and resulting in degradation of tissues. This degradation in turn produces inflammation, which leads to the expression of more cytokines; the cycle becomes more and more destructive.
It is estimated that over $1 billion is spent by Americans to deal with TMD pain. Of the 7 million people suffering TMD, 2 million will seek medical help. 100,000 people will undergo some sort of surgical procedure. The average age of symptom onset is 18-26 years old. Women are more likely to suffer chronic facial pain and TMD than men by 2:1. Women are 10 times more likely than men to pursue medical help, including surgery.
Current treatment phases include:
Phase 1: Educating the patient about muscle fatigue. Improvement of oral hygiene is stressed. This includes no gum chewing, candy chewing, jaw clenching etc. Soft diets are recommended and non-steroidal anti-inflammatories (NSAIDs) such as ibuprofen and muscle relaxants of the benzodiazepine class are prescribed. Typically only 50% of patient will improve at this stage. The rest progress to Phase 2.
Phase 2: Continuation of NSAIDs and benzodiazepine. A bite splint is usually prescribed to improve the joint occlusion. Typically, of the 50% from phase 1 that did not improve, only 25% of patients will improve during this phase. The rest progress to Phase 3.
Phase 3: Continuation of NSAIDs and a splint. Ultrasonic therapy, electrogalvanic stimulation or biofeedback is added to the treatment regiment. No one of the mentioned treatments has been shown to be better than the other. Of the patients who progress to this phase, less than 15% improve. The rest progress to Phase 4.
Phase 4: A series of approaches such as steroid injections, physical therapy, psychological counseling, and eventually, surgery. Less than 50% of these patients improve.
The treatment regiment is essentially, NSAIDs, progression into cortisone injections, followed by surgery. The shortcomings of these methods are as follows:                NSAIDs only help about 50% of the patient who use them.        Cortisone and other steroids injected into the soft tissues of the TM joint have been shown to have a deleterious effect on the soft tissues. Though pain subsides after a steroid injection, the steroid causes degradation and eventually failure of the TM joint.        Surgery is expensive, invasive, and does not guarantee success in treating pain.        
Polymer gels are currently used to treat pain in various cases of osteoarthritis (OA) of the knee. Three products, SYNVISC® Hylan GF-20 (Genzyme Corporation. Cambridge, Mass.), HYALGAN® Sodium Hyaluronate (Sanofi-Aventis U.S. LLC. New York. N.Y.), and SUPARTZ® Joint Fluid Therapy (Smith & Nephew plc, London, England) have all received FDA approval for treatment of OA in patients who do not respond to NSAIDs. Of these three, SYNVISC® Hylan GF-20 is the most widely used, with sales that currently exceed $127 million annually. Current gels used to treat pain associated with OA of the knee use almost pure solutions of hyaluronic acid (HA), a biological polymer that is native to all mammalian connective tissue. For example, SYNVISC® Hylan GF-20 includes 0.8% HA. Despite their success for treatment of OA of the knee, these products have not been used successfully to treat temporomandibular joint disorders (a.k.a. TMJ or TMD).
The TM joint differs from the knee in several respects. First, from a mechanical perspective, the knee is essentially a “hinge” joint with only two modes of motion: extension and flexion. The TM joint has three modes of motion including elevation/depression, protrusion/retraction, and lateral deviation. In this respect, the TM joint is far more complex than the knee.
The TM joint also appears to handle forces far in excess of the knee joint. Researchers designing knee replacement devices (ACLs, fixation devices, etc.) typically find that in vitro testing of these devices yields force values of 200 to 400 Newtons. In vivo testing yielded 300 Newtons. Bite forces in men and women have been reported at 847 and 597 Newtons respectively.
The TM joint also varies from the knee physiologically. Though both joints are comprised of water, chondrocytes, collagen protein, and glycosoaminoglycans (GAGs), the relative ratios of these materials are very different. Whereas the knee is comprised of Type II collagen (>95% of the total collagen in the knee), the TM joint is mostly Type I collagen, with some Type III collagen. Both the knee and TM joint have GAGs present, the most abundant being chondoitin sulfate, which accounts for about 80% of the GAGs of these joints, but the TM joint's hyaluronic acid concentration tends to be only 5% of GAGs, while the hyaluronic acid concentration in the knee ranges from 10-15% of the GAGs.
In the knee, where the hyaluronic acid concentration relative to the water content is about 1%-1.5%, it is easy to understand why the commercial products that are used to treat OA of the knee tend to be in the 10-15 mg/ml range (1% =10 mg/ml). For example, HYALGAN® Sodium Hyaluronate is 10 mg/ml hyaluronic acid, and SYNVISC® Hylan GF-20 is 8 mg/ml. It is also easy to understand why simply using these products in the treatment of ID/OA TMD may not be successful since they do not take into account the unique characteristics of the TM joint.
In the knee, products comprised of hyaluronic acid appear to slow the progression of early stage OA. It is believed this is due to two possible factors. First, it is widely held that hyaluronic acid's role is mostly mechanical, hence its classification as a medical device. Repeated injection into the knee delivers moisture which is typically lacking in OA tissues, and acts as a physical barrier to the inflammatory chemicals that OA tissues tend to release. Also, since low molecular weight oligosaccharides tend to be markers of OA, it is thought that high molecular weight HA can be re-incorporated into the extracellular matrix of cartilage tissue.
A less popular theory is that the inflammatory chemicals released by OA tissues have significant hyaluronidase activity, and are part of a cycle of destruction in OA tissues resulting in low molecular weight oligosaccharides. If this is the case, hyaluronic acid injections not only provide a physical barrier to inflammatory agents, but may also serve to redirect the activity of these agents by providing excess (sacrificial) substrate for them to consume. As inflammation reduces, less of these chemicals are produced by the OA tissues, and the destructive cycle is broken, or at least slowed to a manageable rate.
Since the HA concentration in the TM joint is about half what it is in the knee, it should come as no surprise that Bertolami et al. observed that injections of HA in OA TM joints had little or no beneficial effect, while injections in patients with reducing displaced disk (DDR) noted a reduction in pain. Clearly these HA injections were providing a physical benefit such as delivery of moisture and possibly a physical barrier in the DDR patients. Straight HA did not provide the full benefit noted by patients with OA of the knee.
This difference between the efficacy of the HA in the knee and TM joint can potentially be explained by examining the latest biochemical research on the TM joint published in Cells Tissues Organs, Volume 169, No. 3, pp. 248-264. Two articles have for the first time described the inflammatory agents and degenerative pathways of these agents. In particular, Puzas et al., and Kacena et al., detail the role of inflammatory cytokines such as IL-1β, TNF-α and their expression of matrix metalloproteinases (MMPs). Kacena clearly showed that human patients who suffered TMJ disorders had significantly elevated level of both IL-1β and TNF-α in their TM joint synovial fluid.
IL-1β and TNF-α bind to the AP-1 binding sites. These sites regulate the production of MMPs 1, 3, 9, and 10. Puzas et al. showed in their study of a mouse model with OA of the TM joint, that not only were the cytokines present, but many of the MMPs were present also. In particular, a Zymographic analysis of the MMP activity in the TMJ disc cells of the mouse showed that MMPs in the molecular weight range close to 58 kD were present. This was a very intense band that appeared to vary between the molecular weights of 50 to 60 kD. This band corresponds to MMP1 (MW=57-52 kD), MMP3 (MW=55-60 kD) and MMP10 (MW=55-60 kD). All of these MMPs have hyaluronidase activity. MMP1 has a very specific type I collagenase activity.
Given the state of the art, there is a definite need for a novel composition to treat joint pain such as TMJ and other inflammatory and degenerative joint diseases.